OVOL2-Mediated ZEB1 Downregulation May Prevent Promotion of Actinic Keratosis to Cutaneous Squamous Cell Carcinoma.

Maho Murata,Takamichi Ito,Masutaka Furue,Kazuhisa Furue,Kazuhiko Yamamura,Yuka Tanaka

doi:10.3390/jcm9030618

Maho Murata, Takamichi Ito + Show 4 more

Open Access

https://doi.org/10.3390/jcm9030618

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Abstract

Progression of actinic keratosis (AK) to cutaneous squamous cell carcinoma (cSCC) is rare. Most cases of AK remain as intraepidermal lesions, owing to the suppression of the epithelial-to-mesenchymal transition (EMT). Ovo-like transcriptional repressor 1 (OVOL1) and ovo-like zinc finger 2 (OVOL2) are important modulators of EMT in some tumors, but their roles in skin tumors remain elusive. This study elucidated the roles of OVOL1/2 in AK and cSCC using 30 AK/30 cSCC clinical samples, and an A431 human SCC cell line using immunohistochemistry and molecular biological approaches. Immunohistochemically, OVOL1/2 were upregulated in AK and downregulated in cSCC. Meanwhile, EMT-related factors, vimentin and zinc finger E-box binding homeobox 1 (ZEB1) were downregulated in AK and upregulated in cSCC. Moreover, ZEB1 expression was higher in tumors in which OVOL2 expression was low. Thus, we observed an inverse association between OVOL2 and ZEB1 expression in AK and cSCC. Although knockdown of OVOL1 or OVOL2 increased the mRNA and protein levels of ZEB1, only OVOL2 knockdown increased the invasive ability of A431. In conclusion, OVOL2 inhibits ZEB1 expression and may inhibit the promotion of AK into cSCC. OVOL2/ZEB1 axis may be a potential target for preventing the development of cSCC.

Highlights

Actinic keratosis (AK) and cutaneous squamous cell carcinoma are common types of precancerous and cancerous skin lesions, whose prevalence is increasing in the context of population aging [1]
To clarify the clinical significance of Ovo-like transcriptional repressor 1 (OVOL1), ovo-like zinc finger 2 (OVOL2), zinc finger E-box binding homeobox 1 (ZEB1) and vimentin in AK and cutaneous squamous cell carcinoma (cSCC), we examined their expression in 30 AK, 30 cSCC, and 13 perilesional normal skin using immunohistochemical staining
In AK, cells budding into the dermis, which were at the forefront of the epithelial-to-mesenchymal transition (EMT) process, were strongly positive for OVOL2 (Figure 1B and Supplementary Figure S3)

Summary

Introduction

Actinic keratosis (AK) and cutaneous squamous cell carcinoma (cSCC) are common types of precancerous and cancerous skin lesions, whose prevalence is increasing in the context of population aging [1]. Most cases of AK remain intraepidermal lesions and the progression of AK to cSCC is rare [3,4]. Changes in AK start at the basal layer in the interfollicular epidermis [1,5]. The transition from AK to cSCC is suggested to occur in one of two ways: through direct dermal invasion of the atypical cells found only in the basal layer of AK, or through secondary dermal invasion after the atypical cells have extended throughout the epidermis [5]. Most AK cases are restricted to the epidermis for a long time, suggesting the existence of a potent mechanism that suppresses the epithelial-to-mesenchymal transition (EMT)

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